A shear-restricted pathway of platelet procoagulant activity is regulated by IQGAP1
A shear-restricted pathway of platelet procoagulant activity is regulated by IQGAP1
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DOI：
10.1074/jbc.m402561200
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发表时间：
2004-05-21
影响因子：
4.8
通讯作者：
Jesty, J
中科院分区：
文献类型：
--
作者：
Bahou, WF;Scudder, L;Jesty, J
循环血小板通过粘附和聚集事件以及通过为凝血酶原酶复合物组装和凝血酶生成提供必要的促凝血表面来调节止血反应的初始阶段。调节血小板促凝血活性的信号通路在很大程度上是未知的，尽管它们不同于与纤维蛋白原连接到构象活性α（IIB）β（3）整联蛋白相关的血小板聚集信号。我们描述了一种新的细胞内信号转导机制，涉及血小板IQGAP 1，特别是调节血小板促凝血活性的发展条件下的机械剪切力。当受到16达因/cm（2）（剪切速率为1600 s（-1））的生理剪切应力激活时，IQGAP 1缺陷的小鼠血小板与野生型同窝对照相比表现出凝血酶原酶活性增加（p < 0.0001），相当于正常剪切应力的2.5倍，或相当于冠状动脉狭窄程度的40%。过度的凝血酶原酶活性与增强的血小板微泡形成（细胞骨架蛋白水解）无关，并且独立于细胞内钙释放[Ca 2 +]（i）发生，但它特异性地与α-颗粒胞吐途径偶联，对氨基磷脂暴露无伴随影响。这些观察结果将血小板IQGAP 1确定为正常止血的重要调节剂，并确定为控制血小板促凝血功能的适当药理学靶点。
Circulating blood platelets regulate the initial phase of the hemostatic response through adhesive and aggregatory events and by providing the necessary procoagulant surface for prothrombinase complex assembly and thrombin generation. The signaling pathway(s) that regulate platelet procoagulant activity are largely unknown, although they are distinct from platelet aggregatory signals linked to fibrinogen ligation to the conformationally active alpha(IIB)beta(3) integrin. We describe a novel intracellular signaling mechanism involving platelet IQGAP1 that specifically regulates the development of platelet procoagulant activity under conditions of mechanical shear stress. Murine platelets that are deficient in IQGAP1 demonstrate increased prothrombinase activity compared with wild-type littermate controls when activated by a physiological shear stress of 16 dynes/cm(2) (shear rates of 1600 s(-1)) (p < 0.0001), corresponding to similar to 2.5 times the normal shear stress, or similar to 40% degree of stenosis in coronary arteries. The exaggerated prothrombinase activity is not associated with enhanced platelet microvesiculation ( cytoskeletal proteolysis) and occurs independently of the intracellular calcium release, [Ca2+](i), but it is specifically coupled to the alpha-granule exocytic pathway without concomitant effects on aminophospholipid exposure. These observations identify platelet IQGAP1 as an important modulator of normal hemostasis and as an appropriate pharmacological target for control of platelet procoagulant function.